Monday, March 29, 2010

Genetic reductionism, part I -- the path from broad to narrow?

What geneticists used to know
We've been reading the writings of some of the early geneticists, and have been struck by how many of the original concepts and how much of the jargon are still in use even after a century of major discoveries. Even many of the names TH Morgan gave to fruit fly genes in the 1910s and 20s, without knowing anything about the structure of genes and how they work, are still in use today. Their names, in fact, are a major reflection of the way that science actually works.

The figure to the left, a map of the four fruit fly chromosomes, with gene names, is from Morgan's book, The Theory of the Gene, published in 1926. In that book, he outlined his theory as follows:
The theory states that the characters of the individual are referable to paired elements (genes) in the germinal material that are held together in a definite number of linkage groups; it states that the members of each pair of genes separate when the germ-cells mature in accordance with Mendel's first law, and in consequence each germ-cell comes to contain one set only; it states that the members belonging to different linkage groups assort independently in accordance with Mendel's second law; it states that an orderly interchange--crossing-over--also takes place, at times, between the elements in corresponding linkage groups; and it states that the frequency of crossing-over furnishes evidence of the linear order of the elements in each linkage group and of the relative position of the elements with respect to each other.
Note that his theory of the gene rests almost entirely on the work of Mendel, fifty years before. By good luck (given what was known at the time), Mendel studied traits that were not closely located ('linked') on the same chromosome, so that Morgan's group was working with and expanding on rather then testing or challenging Mendel's theory.

Mendel knew that systematic hybridization experiments would elucidate patterns of transmission of the 'elements' that were responsible for traits. But only some traits; others were too complicated, and didn't follow the same patterns. Mendel tried the same approach in other plants and found that some did not follow his rules, in fact; but the doubts that led to were overlooked given his overall success. We now know that traits he avoided did not 'segregate' in the way the traits he chose did, because they are due to the joint contribution of many different genes, known today as polygenes.

Morgan presents his theory of the gene, and then adds the following, and this is important with respect to how they could know as much as they did without understanding much at all about genes:
These principles, which, taken together, I have ventured to call the theory of the gene, enable us to handle problems of genetics on a strictly numerical basis, and allow us to predict, with a great deal of precision, what will occur in any given situation.
By 'strictly numerical', he meant that one need not understand what the genes were, in chemical terms, or how they worked. The rules of inheritance were made manifest through the relative numbers of different types of offspring of a given set of parents -- which Mendel first showed, and others built upon.

But Morgan didn't suppose that all traits were due to single genes. He was aware that most were due to many genes, and that it was likely that most genes do more than one thing.
A man may be tall because he has long legs, or because he has a long body, or both. Some of the genes may affect all parts, but other genes may affect one region more than another. The result is that the genetic situation is complex and, as yet, not unraveled. (The Theory of the Gene, p 294).
And, these early geneticists also knew about the fundamental contribution of the environment. Morgan ends the paragraph above with this sentence: "Added to this is the probability that the environment may also to some extent affect the end-product."

A student of Morgan's, A.H. Sturtevant, in his A History of Genetics (1965), says:
With Johannsen [who introduced the words "gene", "genotype" and "phenotype" in the early 1900's] it became evident that inherited variations could be slight and environmentally produced ones could be large, and that only experiments could distinguish them.
In 1902 Bateson pointed out that it should be expected that many genes would influence such a character as stature, since it is so obviously dependent on many diverse and separately varying elements. This point of view was implied by Morgan in 1903 (Evolution and Adaptation, p. 277), and by Pearson in 1904.
This is among other early examples he offers. Even the most widely used genetics textbook in the 20s and 30s, a book in fact that helped school the Nazis (and a chilling read today), described variation in traits that were due to environmental factors. That book was Human Heredity, by Baur, Fischer and Lenz, first published in Germany in 1921, and revised a number of times. Two of their examples of traits with environmental contributions, are pictured to the left. The pigs in the top photo to the left are from the same litter. The smaller one was poorly nourished, while the larger one was well-fed. As for the rabbits:
Among rabbits, for instance, there are two somewhat similar races, one of which is pure white with pink eyes, while the other (the "Himalayan" rabbit) though mainly white and whit pink eyes, has very dark fur on the ears, paws, tail, and nose. The colour of the fur in this latter race is modifiable by temperature. If an area of its skin be kept cool, which can easily be effected simply by shaving a part, all the new hairs that grown upon the cooled area have a dark tint. Fig. 6 shows how a patch which had been thus shaved has been covered with dark hair. But as soon as the fur has regrown, so that the area of skin is now protected by it from the cold, all the new hairs which subsequently grow in the area are white, as before, so that the dark tint of the shaved area gradually disappears. It would be easy enough, by shaving the whole surface of the body, to provide one of thees rabbits temporarily with a dark-tinted fur throughout... P 33-34.
So, how did this broad view of genetics become so much narrower as the field matured, so that genetic reductionism that now predominates to a great extent? Indeed, the Human Genome Project and its ongoing sequels epitomize this approach, as its supporters promised that knowing our genes would lead directly to disease prediction (and prevention, and even dramatically increased longevity as a result). Whether this was truly believed, or was cynical spin to get funding -- in fact, it was a mixture of both -- even the intellectual forebears of today's geneticists knew it was wrong.  Or was the early view never as broad as it seems?

In our next couple of posts we'll have some ideas on this. You may disagree, or have other ideas, and if so, we'd love to hear them.

This post was stimulated by work on a paper about the developmental genetics of complex traits like the mammalian skull, and by interactions Ken had on his recent trip to the University of Minnesota, with two philosophers of science Ken Waters and Alan Love.

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